The present invention relates to non-invasive methods and devices for determining the level of glucose in a body fluid of a subject.
There are numerous reasons for determining the level of glucose present in body fluid of a subject. In the case of a person suffering from diabetes, it is often necessary to determine the glucose level in blood daily, or even more frequently. Non-invasive approaches to determination of blood glucose levels have been suggested in the patent literature. For example, U.S. Pat. No. 5,036,861 (issued to Sembrowich et al. on Aug. 6, 1991) describes a wrist-mountable device having an electrode which measures glucose present in sweat at the skin surface. U.S. Pat. No. 5,222,496 (issued to Clarke et al. on Jun. 29, 1993) describes an infrared glucose sensor mountable, for instance, on a wrist or finger. U.S. Pat. No. 5,433,197 (issued to Stark on Jul. 18, 1995) describes determination of blood glucose through illuminating a patient""s eye with near-infrared radiation. U.S. Pat. Nos. 5,115,133, 5,146,091 and 5,197,951 (issued to Knudson on May 19, 1992, Sep. 8, 1992 and Jan. 19, 1993, respectively) describe measuring blood glucose within blood vessels of a tympanic membrane in a human ear through light absorption measurements. The specifications of all of these patents are incorporated herein by reference.
The most common current approaches to determining blood glucose levels still appear to involve obtaining a sample of the person""s blood and then measuring the level of glucose in the sample. These approaches will not be reviewed here except to say that obtaining the blood sample necessarily involves an invasive technique. Generally, the person""s skin is broken or lanced to cause an external flow of blood which is collected in some fashion for the glucose level determination. This can be both inconvenient and distressful for a person and it is an object of the present invention to avoid the step of obtaining a blood sample directly, at least on a routine or daily basis.
It is known that skin tissue, when immersed in an aqueous glucose solution, equilibrates linearly with the concentration of external glucose (xe2x80x9cGlucose entry into the human epidermis. I. The Concentration of Glucose in the Human Epidermisxe2x80x9d, K. M. Halprin, A. Ohkawara and K. Adachi, J. Invest. Dermatol., 49(6): 559, 1967; xe2x80x9cGlucose entry into the human epidermis. II. The penetration of glucose into the human epidermis in vitroxe2x80x9d, K. M. Halprin and A. Ohkawara, J. Invest. Derm., 49(6): 561, 1967). It has also been shown that skin glucose can vary in synchrony with blood level glucose during standardized tolerance testing in vivo (xe2x80x9cThe cutaneous glucose tolerance test I. A rate constant formula for glucose disappearance from the skinxe2x80x9d, R. M. Fusaro, J. A. Johnson and J. V. Pilsum, J. Invest. Dermatol., 42: 359, 1964; xe2x80x9cThe cutaneous glucose tolerance testxe2x80x9d, R. M. Fusaro and J. A. Johnson, J. Invest. Dermatol., 44: 230, 1965). It is also known for equilibration of glucose levels to occur between blood and interstitial fluids in contact with blood vessels (xe2x80x9cA microdialysis method allowing characterization of intercellular water space in humanxe2x80x9d, P. Lonnroth, P.-A. Jansson and U. Smith, The American Journal of Physiology, 253 (Endocrinol. Metab., 16): E228-E231, 1987; xe2x80x9cAssessment of subcutaneous glucose concentration; validation of the wick technique as a reference for implanted electrochemical sensors in normal and diabetic dogs,xe2x80x9d U. Fischer, R. Ertle, P. Abel, K. Rebrin, E. Brunstein, H. Hahn von Dorsche and E. J. Freyse, Diabetologia, 30: 940, 1987). Implantation of dialysis needles equipped with glucose sensors has shown that orally ingested glucose load is reflected by parallel changes in skin tissue glucose.
Radio frequency spectroscopy using spectral analysis for in vitro or in vivo environments is disclosed in WO 9739341 (published Oct. 23, 1997) and WO 9504496 (published Feb. 16, 1995). Measurement of a target chemical such as blood glucose is described.
The present invention is a method and apparatus for non-invasively monitoring levels of glucose in a body fluid of a subject. Typically, blood glucose levels are determined in a human subject.
In a preferred embodiment, the invention is a method for non-invasively monitoring glucose in a body fluid of a subject in which the method includes steps of measuring impedance between two electrodes in conductive contact with a skin surface of the subject and determining the amount of glucose in the body fluid based upon the measured impedance. Typically, the body fluid in which it is desired to know the level of glucose is blood. In this way, the method can be used to assist in determining levels of insulin administration.
The step of determining the amount of glucose can include comparing the measured impedance with a predetermined relationship between impedance and blood glucose level, further details of which are described below in connection with preferred embodiments.
In a particular embodiment, the step of determining the blood glucose level of a subject includes ascertaining the sum of a fraction of the magnitude of the measured impedance and a fraction of the phase of the measured impedance. The amount of blood glucose, in one embodiment, is determined according to the equation: Predicted glucose=(0.31)Magnitude+(0.24)Phase where the impedance is measured at 20 kHz.
In certain embodiments, impedance is measured at a plurality of frequencies, and the method includes determining the ratio of one or more pairs of measurements and determining the amount of glucose in the body fluid includes comparing the determined ratio(s) with corresponding predetermined ratio(s), i.e., that have been previously correlated with directly measured glucose levels.
In certain embodiments, the method of the invention includes measuring impedance at two frequencies and determining the amount of glucose further includes determining a predetermined index, the index including a ratio of first and second numbers obtained from first and second of the impedance measurements. The first and second numbers can include a component of said first and second impedance measurements, respectively. The first number can be the real part of the complex electrical impedance at the first frequency and the second number can be the magnitude of the complex electrical impedance at the second frequency. The first number can be the imaginary part of the complex electrical impedance at the first frequency and the second number can be the magnitude of the complex electrical impedance at the second frequency. The first number can be the magnitude of the complex electrical impedance at the first frequency and the second number can be the magnitude of the complex electrical impedance at the second frequency. In another embodiment, determining the amount of glucose further includes determining a predetermined index in which the index includes a difference between first and second numbers obtained from first and second of said impedance measurements. The first number can be the phase angle of the complex electrical impedance at the first frequency and said second number can be the phase angle of the complex electrical impedance at the second frequency.
The skin site can be located on the volar forearm, down to the wrist, or it can be behind an ear of a human subject. Typically, the skin surface is treated with a saline solution prior to the measuring step. An electrically conductive gel can be applied to the skin to enhance the conductive contact of the electrodes with the skin surface during the measuring step.
The electrodes can be in operative connection with a computer chip programmed to determine the amount of glucose in the body fluid based upon the measured impedance. There can be an indicator operatively connected to the computer chip for indication of the determined amount of glucose to the subject. The indicator can. provide a visual display to the subject.
In certain embodiments, the computer chip is operatively connected to an insulin pump and the computer chip is programmed to adjust the amount of insulin flow via the pump to the subject in response to the determined amount of glucose.
Electrodes of a probe of the invention can be spaced between about 0.2 mm and about 2 cm from each other.
In another aspect, the invention is an apparatus for non-invasive monitoring of glucose in a body fluid of a subject. The apparatus includes means for measuring impedance of skin tissue in response to a voltage applied thereto and a microprocessor operatively connected to the means for measuring impedance, for determining the amount of glucose in the body fluid based upon the impedance measurement(s). The means for measuring impedance of skin tissue can include a pair of spaced apart electrodes for electrically conductive contact with a skin surface. The microprocessor can be programmed to compare the measured impedance with a predetermined correlation between impedance and blood glucose level. The apparatus can include means for measuring impedance at a plurality frequencies of the applied voltage and the programme can include means for determining the ratio of one or more pairs of the impedance measurements and means for comparing the determined ratio(s) with corresponding predetermined ratio(s) to determine the amount of glucose in the body fluid.
The apparatus preferably includes an indicator operatively connected to the microprocessor for indication of the determined amount of glucose. The indicator can provide a visual display for the subject to read the determined amount of glucose. It is possible that the indicator would indicate if the glucose level is outside of an acceptable range.
In a particular embodiment, the microprocessor is operatively connected to an insulin pump and the apparatus includes means to adjust the amount of insulin flow via the pump to the subject in response to the determined amount of glucose.
The apparatus can include a case having means for mounting the apparatus on the forearm of a human subject with the electrodes in electrically conductive contact with a skin surface of the subject.
In a particular embodiment, the apparatus includes means for calibrating the apparatus against a directly measured glucose level of a said subject. The apparatus can thus include means for inputting the value of the directly measured glucose level in conjunction with impedance measured about the same time, for use by the programme to determine the blood glucose level of that subject at a later time based solely on subsequent impedance measurements.
A microprocessor of the apparatus can be programmed to determine the glucose level of a subject based on the sum of a fraction of the magnitude of the measured impedance and a fraction of the phase of the measured impedance. In a particular embodiment, the apparatus is set to measure impedance at 20 kHz and the microprocessor is programmed to determine the glucose level of a subject based on the equation: Predicted glucose=(0.31)Magnitude+(0.24)Phase.